1. Field of the Invention
The invention in the field of medicinal chemistry, pharmacology and medicine, related to novel compounds, and derivatives of known compounds and methods for their use in the treatment of bladder disease, particularly urinary incontinence, by intravesical instillation.
2. Description of the Background Art
Urinary incontinence afflicts a large and diverse patient population. The United States Department of Health and Human Services Agency for Health Care Policy and Research (AHCPR) reviewed the literature on the incidence of urinary incontinence, the clinical, psychological, and social impact of the disorder, as well as monetary costs to society. Clinical Practice Guideline for Urinary Incontinence in Adults (AHCPR 92-0038, 1992; abbreviated xe2x80x9cAHCPR 1992xe2x80x9d). Estimates vary, but approximately 15% of a randomly selected group of women perceived urinary incontinence as a social or hygienic problem. For noninstitutionalized individuals older than 60, the prevalence ranges from 15 to 30%, with women having twice the prevalence of men. Among those identified, approximately 25% have daily or weekly episodes of incontinence. Among nursing facility residents, the incidence is 50% or greater, with episodes occurring more than once per day. The annual direct costs of care based on 1987 dollars was estimated as $7 billion in the community and $3.3 billion in nursing homes.
Anticholinergic Therapy and the Treatment of Urinary Incontinence
For a detailed description of anticholinergic agents and their use in treating various diseases, see: Faye, W. P., PRINCIPLES OF MEDICINAL CHEMISTRY, Lea and Fibiger, 1989, pp. 328-348; Gilman, A. G. et al., (eds), THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 8th Edition, Macmillan Publishing Co., New York, 1990, chapter 8, pp. 150-165, both of which references are hereby incorporated by reference herein).
Contraction of the bladder detrusor muscle is mediated by cholinergic muscarinic receptors. Muscarinic receptors are divisible into several subtypes which are distinguishable based on binding of selective ligands. These muscarinic receptor subtypes exist in differing concentrations in different tissues. The M3 muscarinic receptors predominate in the detrusor muscle, having about a ten-fold greater density than M1 or M2 receptor subtypes (Kondo, S. et al., Urol. Int 54:150-153, 1995; Kondo, S. et al., J. Smooth Muscle Res. 29:63-68, 1993; Shishido, K. et al., 26th Meeting of the International Continence Society. Neurourol and Urodynamics 15:313-314, 1996 (Abstract #36)). The present invention targets these receptors by administration of novel antimuscarinic agents via a catheter to the bladder to attain prolonged maintenance of bladder control in otherwise incontinent patients.
The drug oxybutynin chloride (FIG. 1K) (4-diethylamino)-2-butynyl-xcex1-cyclohexyl-xcex1-hydroxybenzeneacetate HCl; trade name Ditropan(copyright)) is the current standard anticholinergic therapeutic agent for urinary incontinence. Relief of symptoms in neurogenic bladder disorders are thought to result from its combined anticholinergic, antispasmodic, and local anesthetic activities. The anticholinergic side-effects limit its acceptability to many patients. In fact, use of oral oxybutynin is frequently discontinued because of the unpleasantness of the side effects (Thuroff et al, J. Urol. 145:813-817, 1991).
For treatment of detrusor overactivity, AHCPR 1992 (since reissued with minor revisions) recommended oxybutynin at oral doses of 2.5-5 mg, to be taken 3-4 times per day. At the time of agency review, 5 of 6 randomized controlled studies had reported superiority of oxybutynin to placebo. One exception was a study of elderly nursing home residents which used less frequent administration of the drug.
The dose-related anticholinergic side effects of oral oxybutynin include marked xerostomia, dry skin, blurred vision, nausea, and constipation. Severe mouth dryness occurred in 84% of subjects receiving 5 mg/kg four times/day (AHCPR, 1992). Side effects could be minimized by administration of this compound via clean intermittent self-catheterization directly into the bladder (intravesical administration). However, this required at least daily self-catheterization. Better restoration of bladder control required multiple catheter insertions each day. A series of papers reported beneficial effects in different patient groups. The following are representative: Brendler, J. Urol. 141:1350-1352, 1989; Weese, D. L. et al., Urology 41:527-530, 1993; Greenfield, S. P. et al., J. Urol. 146:532-534, 1991; Madersbacher, M. et al., Paraplegia 29:84-90, 1991).
A double-blind, randomized, placebo-controlled, parallel group study of intravesical oxybutynin was reported at a recent conference (Krishnan, K. R., Neurourol and Urodyn. 15:307-308, 1996). There was some systemic absorption of the drug following intravesical administration, but the incidence of adverse side effects was low. However, the difficulty in patients being able to continue a typical intravesical instillation protocol is illustrated by Weese et al. (supra), which reported that instillation of the drug two to three times daily via clean self intermittent catheterization resulted in 21% of the patients dropping out due to inability to tolerate the catheterization or to difficulty in retaining the drug solution in the bladder.
McPherson et al. (U.S. Pat. No. 5,001,160) described antimuscarinic agents for the treatment of neurogenic bladder disease. The compounds disclosed were said to have longer durations of action than did older anticholinergic agents such as methantheline and propantheline. The majority of neurogenic bladder patients have spastic or hypertonic conditions. Clinicians generally aim to convert this condition to hypotonia as a way to treat the primary problem of incontinence. Thus, when the condition has been xe2x80x9cconvertedxe2x80x9d to hypotonia, it can be managed in a straightforward way by intermittent catheterization. For those patients who cannot be converted from the hypertonic to the hypotonic state and who still need to urinate every hour, longer term treatment with an anticholinergic drug (muscarinic receptor antagonists) was said to be necessary. As noted above, the current drug of choice for this treatment is oxybutynin which is considered to be better than the older anticholinergics. McPherson et al. (supra) disclosed 1-aryl-1-hydroxy-1-R1-3-(4-R2-1-piperazinyl)-2-propanones. In preferred compounds, R1 was a cycloalkyl of 3-6 carbons, most preferably cyclohexyl or cyclobutyl. R2 was lower alkyl, benzyl, para-substituted benzyl or cinnamyl. The most preferred compound was 1-cyclobutyl-1-hydroxy-1-phenyl-3-(4-benzyl-1-piperazinyl)-2-propanone. For parenteral administration, the compounds were prepared in conventional aqueous injection solutions. This document disclosed that extemporaneous injection solutions could be prepared from sterile pills, granules or tablets and contained diluents, dispersing and surface active agents, binders and lubricants as well as the anticholinergic compound.
Tolterodine is a new antimuscarinic of comparable duration of action which is reported to cause a lower incidence of dry mouth (xcx9c9%). The following dose-related side effects were observed with tolterodine: diminished stimulated salivation after 3.2 mg, increased heart rate after 6.4 mg, and altered the nearpoint of vision after 12.8 mg. Six of 8 subjects reported micturition difficulties after a dose of 12.8 mg
Other Drugs in the Treatment of Urinary Incontinence
Terodiline has both anticholinergic and calcium antagonist properties, and effectively reduces abnormal bladder contractions caused by detrusor instability (Langtry, HD et al., Drugs 40:748-761 (1990)). When administered to adult patients with urge incontinence (generally as a 25 mg dose twice daily), terodiline reduced micturition frequency and incontinence episodes. Bladder volume at first urge and bladder capacity were increased. Children with diurnal enuresis respond similarly to a daily 25 mg dose. Terodiline at 50 mg/day was said to be preferred by patients when compared with emepronium 600 mg/day or flavoxate 600 mg/day, and tended to reduce voluntary micturition frequency and episodes of incontinence more effectively than these other drugs. Anticholinergic side effects were the most common ones reported.
Anhydroecgonine Derivatives as Anticholinergic Agents
Anhydroecgonine methyl ester (AEME), the primary pyrolysis product of cocaine, (B. R. Martin et al., J. Anal. Toxicol. 13:158 (1989)) is structurally similar to arecoline and anatoxin A. See FIG. 1J for a general structure of AEME compounds. While investigating the effects of crack smoking, the present inventor and his colleagues noted that experimental animals frequently showed bronchoconstriction. This observation led the inventors to focus on AEME and other anhydroecgonine esters (AEE) as bronchoconstrictors when given by inhalation. The present inventor initially studied this agent in isolated guinea pig tracheal rings and found, unexpectedly (in view of the bronchoconstricting action of cocaine), that AEME lacked cholinergic agonist activity. Even more surprisingly, AEME turned out to be a potent non-competitive muscarinic antagonist in vitro. The antagonistic effects were insurmountable by the addition of increasing amounts of acetylcholine (ACh). Furthermore the anticholinergic effects were irreversible, so that tissue exposed to AEME could not later attain its original magnitude of contraction. These findings were unexpected because AEME, resembling arecoline and anatoxin in structure, should have behaved as a cholinergic agonist. The present inventor and his colleagues described AEE compositions, derivatives or analogues thereof having anticholinergic activity, methods of preventing or inhibiting cholinergic responses and methods of using the compositions to prevent or treat diseases associated with bronchoconstriction (U.S. Pat. No. 5,552,407 and co-pending application U.S. Ser. No. 08/706,105 filed Aug. 30, 1996 (allowed), hereby incorporated by reference in their entirety.
Other Bladder Diseases
Interstitial cystitis (IC), a syndrome occurring primarily in women, is characterized by urinary urgency and frequency, suprapubic pain and petechial bladder mucosal hemorrhages upon distention under general anesthesia. Almost 50% of IC patients also suffer from allergies and irritable bowel syndrome, all of which are exacerbated by stress. One of the prevailing theories to explain IC pathophysiology is the increased number of activated mast cells in the bladder. Mast cells mediate hypersensitivity reactions wherein they are triggered by immunoglobulin E (IgE) and antigen (allergen) to release numerous vasoactive and proinflammatory substances. Mast cells are found in juxtaposition to neurons and are also activated by direct nerve stimulation, as well as by ACh, neurotensin and substance P.
Targeting Parasympathetic Control of Organ Function
In addition to its role in bladder control, the parasympathetic nervous system plays a major role in regulating bronchomotor tone. Thus, lessons learned in the field of pulmonary medicine have assisted the present inventor in conceiving the invention disclosed herein. One drug used to treat respiratory disease such as asthma is the quaternary anticholinergic agent isopropylatropine bromide, also called ipratropium bromide (Atrovent(copyright)) (Gross, H. J., New Eng. J. Med. 319:486-494 (1988); Higgenbottam, T. W. et al., eds., Postgrad. Med. J. 63 (Suppl):1-93 (1987)). This agent, administered by inhalation, is poorly absorbed so that it exerts its effects primarily, and in a limited manner, on the internal surfaces of the lungs. Thus, a major advantage of ipratropium for respiratory therapy is the possibility of reaching elevated regional tissue (lung) concentrations with few systemic anticholinergic effects. Another advantage of ipratropium compared to other anti-asthmatic drugs is its duration of action. Its pharmacologic effect becomes maximal in about an hour, and persists for several hours. Partly based on the foregoing, the present inventor conceived of the types of compounds useful for long duration therapy of bladder disease.
Quinuclidinol Derivatives as Anticholinergic Agents
Quinuclidinyl benzilate (QNB; FIG. 1B)) is a well-known anticholinergic agent that was originally prepared by Sternbach and colleagues at Hoffman LaRoche in the 1950""s (Sternbach et al., J. Amer. Chem. Soc. 74:2215-2218 and 2219-2221 (1952); U.S. Pat. No. 2,648,667). QNB was studied by the military due to its central psychotomimetic potency, as discussed below. The present invention includes novel quinuclidinol derivatives and methods for using them, as well as a new use for known quinuclidinol compounds in the treatment of bladder diseases.
Gibson, R. E., et al., J. Nucl. Med. 20:865-870 (1979) determined the distribution of [3H] QNB and its methiodide salt in rat, guinea pig, and rabbit. Accumulation in the myocardium of up to 2% of the injected dose per gram of tissue was observed with both compounds, providing heart-to-blood ratios of xcx9c30 and heart-to-lung ratios of xcx9c4. The accumulation in the heart was blocked (89%) by preinjection of atropine. The distribution of tritium in the rabbit heart corresponds to the muscarinic receptor density as determined in vitro. Calculated theoretical maxima for the bound-to-free ratio, based on in vitro equilibrium of binding isotherms, were in reasonable agreement with the experimental results. Because of the high accumulation in the heart with low serum concentration, the authors concluded that the methiodide salt of QNB represents an ideal parent structure for the design of receptor binding xcex3-emitting radiopharmaceuticals for imaging of the myocardium.
Rzeszotarski, W. J., et al., J. Med. Chem. 25:1103-1106 (1982) measured the affinities of a number of synthetic QNB analogs to muscarinic receptors from rat or dog ventricular muscle. It was determined that the muscarinic receptor can, to a different degree, accommodate either a halogen in the ortho, meta, or para position of one phenyl ring or could accommodate replacement of one phenyl ring with an alkyl group. In vitro competition studies showed that the affinities lay within a 270-fold range in the series of compounds tested, from the highest affinity compound, 3-quinuclidinyl-xcex1-hydroxy-xcex1-cyclopentylphenyl acetate, to the lowest affinity compound, 3-quinuclidinyl-xcex1-hydroxy-xcex1-2-propargylphenyl acetate.
Waelbroeck, M. et al., Molec. Pharmacol. 40:413-420 (1991), analyzed the competition kinetics of QNB and QNB methiodide enantiomers on muscarinic binding sites of human MV-OK1 neuroblastoma cells (primarily M1), rat cardiac (primarily M2), and rat pancreas (primarily M3). The association rate constants (Ka""s) of the four drugs depended on the receptor subtype and were lower with pancreatic than with cardiac or MV-OK1 binding sites. At each receptor subtype, there were no significant difference between the Ka of the R- and S-enantiomers of either QNB or QNB methiodide. Receptor stereoselectivity, when present, was associated with differences in unlabeled drug Kd""s. The Kd""s varied much more than the Ka""s. Competition kinetic analysis was used to compare either (a) (R)-QNB dissociation from the three receptor subtypes (half-life, 77 min to greater than 340 min; best fit, 40 days) or (b) dissociation of the four drugs from each receptor subtype, with half-lives varying from 1.4 min to 4 hr at M1 receptors, 1.1 to 77 min at M2 receptors and 3.5 min to greater than 340 min at M3 receptors.
In the treatment of bladder disease, there is clearly a need in the art for new agents with improved activity profiles in the same direction as those shown by ipratropium for asthma. Urinary incontinence in particular is in need of new methods of treatment. The present invention is addressed to this need.
Citation of the above documents is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of these documents.
The administration of quaternary anticholinergic agents with prolonged duration of action via a catheter to the bladder results in prolonged maintenance of bladder control in otherwise incontinent patients. Agents with durations of action between a week and a month could be useful for a significant number of patients and perhaps reach distinct groups for whom no satisfactory treatment is currently available.
This invention is directed to methods, chemical compounds and pharmaceutical compositions. The invention includes within its scope compounds yet to be synthesized, and new uses and routes of administration for known compounds. Also included are special kits useful for preparing the drug for administration, for administering it, and for quantifying effectiveness of drug delivery for individual patients.
Thus methods of promoting bladder control in incontinence and other bladder diseases using such compounds constitute a key embodiment of this invention.
The invention provides a compound for treating bladder disease which has improved antimuscarinic activity in the bladder and blocks M3 muscarinic receptors. The compound is preferably a derivative of an antimuscarinic molecule. Formulas for preferred families of compounds are shown in FIGS. 1A-1M. FIGS. 1A-1J and FIG. 1L are quaternary base compounds that are intended to be used as salts, e.g., acid addition salts. It will be understood that when a compound is a quaternary base, the composition to be administered for treatment will always be a salt thereof.
Preferred compounds include derivatives of the following compounds:
N-methyl-3-quinuclidine (FIG. 1A is a quaternary quinuclidinium base),
N-methyl-3-piperidine (FIG. 1C is a 3-piperidinium base),
N-methyl-4-piperidine (FIG. 1D is a 4-piperidinium base),
N-methyl-3-pyrrolidine (FIG. 1E is a pyrrolidinium base),
N-methyl-3-granatanine (FIG. 1F is a granatanium base)
(the IUPAC name for N-methyl-3 granatanol is 9-methyl-9-azabicyclononan-3-ol)
N-methyl-3-tropine (FIG. 1G is a tropinium base),
quaternary anhydroecgonine esters (FIG. 1J)
quaternary derivatives of oxybutynin (FIG. 1K and FIG. 1L),
4-DAMP mustards (FIG. 1N).
A generic class of compounds into which many of the foregoing families of compounds fit is the class: glycolate esters of heterocyclic amino alcohols. These are illustrated in FIG. 1M.
The present invention also provides a method for ameliorating bladder disease, preferably incontinence, in a subject, comprising administering to the subject an effective amount of the pharmaceutical compositions and compounds of the invention. The method is useful for treating any of a number of bladder diseases, including interstitial cystitis and bladder dysfunction associated with any of a number of neurologic diseases, particularly spinal cord injuries or diseases such as spina bifida and myelomeningocele.
The present invention is directed to a method for treating bladder disease in a subject, comprising administering to the bladder of the subject an effective amount of a composition that comprises a chemical compound having the following properties:
(a) binds selectively to muscarinic receptors in the bladder when compared to non-muscarinic receptors, or in another embodiment, is M3 receptor subtype-selective;
(b) is a glycolate ester of a heterocyclic amino alcohol of the general formula 
xe2x80x83or a salt thereof, wherein
R1 is a heterocyclic N-substituted ring or a straight or branched alkyl, alkenyl or alkynyl chain that includes a N atom;
Y is a chemical bond or a lower alkyl group;
Z is O or S;
R2 is OH, Cl, an acyl alcohol group or an acyl chloride group;
R3 and R4 are, independently, a substituted or unsubstituted phenyl, a substituted or unsubstituted cycloalkyl, a straight or branched chain alkyl, alkenyl or alkynyl, and further, one of R3 and R4 may be H.
The compound is delivered to the subject in the form of a pharmaceutical composition which includes a carrier or excipient appropriate for delivery to the bladder, such as a solution for intravesical instillation by catheterization.
Preferably, in this method, the N of R1 is a quaternary N and R2 is OH
In one embodiment, R1 is a heterocyclic N-substituted ring, preferably one selected from the group consisting of 3-piperidinyl, 4-piperidinyl, 3-pyrrolidinyl, 3-quinuclidinyl, 3-granatanyl, 3-tropinyl, 3-granatanyl epoxide and 3-tropinyl epoxide.
When the N is quaternary, the N atom is preferably substituted with a straight or branched C1-C10 alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl or an amidine. xe2x80x9cSubstitutedxe2x80x9d as used throughout includes aryl or heteroaryl substituents. In one embodiment, the quaternary nitrogen atom is substituted with methyl or isopropyl.
In one embodiment, the above method utilizes a compound wherein R1 is an N-methyl quinuclidinyl ring; Y is a chemical bond Z is O; R2 is OH; R3 and 1R4 are each phenyl. This compound is known as methyl QNB (see below). In another preferred method R1 is a quinuclidinyl or N-methyl quinuclidinyl ring, Y is a chemical bond or CH2; Z is O; R2 is OHxe2x80x2 and R3 and R4 are phenyl and cyclopentyl (See xe2x80x9ccompound 3167xe2x80x9d discussed below). In a related embodiment, R1 is an N-methyl-4- piperidyl ring, Y is a chemical bond or CH2; Z is O; R2 is OH; and R3 and R4 phenyl and cyclobutyl (see xe2x80x9ccompound 3580xe2x80x9d, below). In yet another embodiment, R1 is an N-methyl-4-piperidyl ring; Y is a chemical bond or CH2; Z is O; R2 is OH; and R3 and R4 phenyl and cyclopentyl (see xe2x80x9ccompound 3443xe2x80x9d, below).
The present invention also provides a method as above, wherein R1 is 4-piperidinyl in which the N is substituted with Xxe2x80x2; R2 and R4 are phenyl; R3 is H; Xxe2x80x2 is a lower alkyl group optionally halogenated. X is preferably bromoethyl or bromopropyl. In the above, method, the ring N may also be quaternized by substitution with a straight or branched C1-C10 alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl or an amidine.
The present method also utilizes compounds wherein R1 is a chain having the formula 
wherein X1 and X2 are lower alkyl, and X3 is a straight or branched C1-C10 alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl or an amidine. in a preferred embodiment, Y is a chemical bond, Z is O, R2 is OH, R3 and R4 are any of phenyl, cyclohexyl or cyclopentyl, X1 and X2 are ethyl. These compounds are derivatives of oxybutynin.
The present method may also be carried out with a compound as described above, additionally substituted with a reactive or alkylating function on any one of R1, R2, R3 or R4. For example, when R1 is a heterocyclic N-substituted ring, the reactive or alkylating function may be a substituent on the quaternary nitrogen group of the ring (as in a compound described above. In another embodiment, (i) R1 is a heterocyclic N-substituted ring, and, (ii) a reactive substituent of a carbon atom of the ring, preferably in the para position relative to the N, spontaneously cyclizes in solution, thereby generating the alkylating function, for example, an aziridinium ion.
The foregoing methods are useful for treating any of number of bladder disease, but are particularly aimed at people suffering from urge incontinence or interstitial cystitis. The preferred route of administration is by intravesical instillation. This is preferably done at a lower frequency than once daily, preferably once weekly or even less.
The present invention also provides a composition useful for treating bladder disease in a subject, which comprises a chemical compound having the following properties:
(a) binds selectively to muscarinic receptors in the bladder when compared to non-muscarinic receptors, and, preferably is M3 subtype-selective
(b) upon intravesical instillation, suppresses the undesired symptoms of urge incontinence for a period of greater than six hours per dosing, as measured by reduction in (i) detrusor tone or (ii) frequency of micturition or in (iii) prolongation of void time. This duration of action is an important distinguishing feature of the present compounds over the prior art.
(c) is a glycolate ester of a heterocyclic amino alcohol, of the general formula 
xe2x80x83or a salt thereof, wherein
R1 is (i) a heterocyclic N-substituted ring with a quaternary N atom, or (ii) a straight or branched alkyl, alkenyl or alkynyl chain that includes a quaternary N atom;
Y is a chemical bond or a lower alkyl group;
Z is O or S;
R2 is OH, Cl, an acyl alcohol group or an acyl chloride group;
R3 and R4 are, independently, a substituted or unsubstituted phenyl, a substituted or unsubstituted cycloalkyl, a straight or branched chain alkyl, alkenyl or alkynyl, and further, one of R3 and R4 may be H.
with the proviso that said compound is not N-(2-chloroethyl)-4-piperidinyl diphenylacetate, N-(3-chloropropyl)-4-piperidinyl diphenylacetate, N-(2-bromoethyl)-4-piperidinyl diphenylacetate, methyl quinuclidinyl benzilate, methylatropine, methylscopolamine, isopropylatropine, homatropine methylbromide, methantheline bromide, propantheline bromide, anisotropine methylbromide, glycopyrrolate, hexocyclium methylsulfate, isopropamide, mepenzolate bromide, triihexaethylchloride (a number of which compounds are cited using their xe2x80x9cpharmacologicalxe2x80x9d rather than chemical name in Goodman and Gilman""s The Pharmacological Basis of Therapeutics, 8th edition, Gilman et al., eds, 1990, Pergamon Press, New York.
In the above composition, R2 is preferably OH. In another embodiment, R1 is preferably a heterocyclic N-substituted ring, more preferably selected from the group consisting of 3-piperidinyl, 4-piperidinyl, 3-pyrrolidinyl, 3-quinuclidinyl, 3-granatanyl, 3-tropinyl, 3-granatanyl epoxide and 3-tropinyl epoxide.
The quaternary nitrogen atom, above is preferably substituted with a straight or branched C1-C10 alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl or an amidine.
In another embodiment, the composition R1 is 4-piperidinyl in which the N is substituted with Xxe2x80x2; R2 and R4 are any of phenyl, cyclohexyl or cyclopentyl; and R3 is H; wherein X is an optionally halogenated lower alkyl group, most preferably ethylbromide or isopropylbromide.
In another embodiment, R1 above is a chain having the formula 
wherein X1 and X2 are lower alkyl, and X3 is a straight or branched C1-C10 alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl or an amidine.
In one embodiment, Y is a chemical bond, Z is O, R2 is OH, R3 and R4 are any of phenyl, cyclohexyl or cyclopentyl, and X1 and X2 are ethyl.
Also included herein is a composition as above wherein said compound is additionally substituted with a reactive or alkylating function on any one of R1, R2, R3 or R4. When R1 includes heterocyclic N-substituted ring, the reactive or alkylating function can be a substituent on the quaternary N of said ring. Alternatively, the reactive substituent is on a ring carbon atom and produces, by spontaneous cyclization in solution, the alkylating function. In a preferred composition, the alkylating moiety is an aziridinium ion.
Also provided herein is a pharmaceutical composition comprising a composition and above and a pharmaceutically acceptable excipient or carrier for intravesical administration.
In summary, the types of derivatives useful as compositions and in the methods of this invention are (i) a quaternary derivative of molecules of the families discussed above, (ii) a derivative modified to have increased molecular mass by addition of an organic chain including a glycosaminoglycan (GAG), or another moiety that is acceptable in the intravesical environment, to a site of the molecule without adversely affecting binding to muscarinic receptors, particularly of the M3 subtype, or (iii) a derivative to which is added a reactive organic moiety, preferably a mustard group or other alkylating moiety, which renders the derivative capable of binding substantially irreversibly (see definitions, below) to a cell constituent in conjunction with binding of the compound to a bladder M3 muscarinic receptor. Such additional binding may be to a transmembrane G protein, at an opening or on the cell surface.
One class of preferred compounds, which is a subgroup of molecules of FIG. 1G, is substituted quaternary atropines of FIG. 1H, wherein Z is a straight or branched C1-C10 alkyl, alkenyl, alkynyl, or an amidine; and at least one of R1, R2 and R3 is an isothiocyanate, a thiocyanate, a fumaramate methyl ester, a carboxyl methyl ester, a p-azidophenylethylester, a p-isothiocyanatophenylethylester, a p(bromacetoamido)phenylethylester or a 3-iodo-4-azidophenylethylester. Another preferred compound is an epoxide of the substituted quaternary atropine, shown in FIG. 1I with preferred substituents as indicated above.
In another embodiment, the present invention is directed to a composition comprising AEME or a derivative or analogue thereof (FIG. 1J) having anticholinergic activity, which derivative or analogue has the additional property of irreversibility and long duration of action. Preferred compounds of this group have substantially irreversible antimuscarinic anticholinergic activity and derivatives of FIG. 1J wherein R2 is H, C1-C10 alkyl, alkenyl, alkynyl or amidine, and R1 is a reactive organic moiety capable of binding covalently to a constituent of the surface of a cell after the compound has bound to a muscarinic receptor on the cell surface. Preferred compounds of this class having irreversible antimuscarinic activity are selected from the group consisting of anhydroecgonine-2xcex2-carboxylic acid-2-(p-azidophenyl)ethylester, anhydroecgonine-2xcex2-carboxylic acid-2-(p-isothiocyanatophenyl)ethylester, anhydroecgonine-2xcex2-carboxylic acid-2-[p(bromacetoamido)phenyl]ethylester, anhydroecgonine-2xcex2-carboxylic acid-2-(3-iodo-4-azidophenyl)ethylester, anhydroecgonine-2xcex2-isothiocyanate and anhydroecgonine-2xcex2-thiocyanate. However, because of the relative irreversibility and long duration of action of AEME and other AEE""s, this family of compounds may be used herein without the need for derivatizing with a mustard group or with another highly reactive group.
The present invention is further directed to a method of modifying an antimuscarinic compound to become a substantially irreversible inhibitor (see definitions), comprising modifying an antimuscarinic compound with a reactive organic moiety that is capable of binding covalently to a constituent of the surface of a cell after the compound has bound to a muscarinic receptor on the surface of the cell. The antimuscarinic compound so modified may be a member of any class of antimuscarinic compounds that binds to the M3 receptor subtype. Examples include any compounds of FIGS. 1A-N which include antimuscarinic agents of the oxybutynin (FIG. 1K) family, generically described by the formula shown in FIG. 1L, or the 4-DAMP mustard (FIG. 1N) family. However, this invention includes any antimuscarinic agent that can be modified with such a reactive group while preserving its receptor binding and pharmacologic activity.
According to the present invention, these compounds are modified as described above to render them substantially irreversible, which term is defined below.
The present invention is also directed to a pharmaceutical composition useful for treating and inhibiting bladder disease, preferably incontinence, in a subject comprising (a) an antimuscarinic agent or a derivative or analogue thereof as described above; and (b) a pharmaceutically acceptable carrier or excipient for intravesical instillation. Preferred additions to such compositions are materials which enhance viscosity or promote the entry of the active agent into the bladder wall, such as carboxymethyl celluloses and, particularly, GAGs.
In a related embodiment, the treatment includes the physical or pharmacological creation of a depot/slow release compartment for the composition. This can be achieved, for example, by deliver of the agent using liposomes or othe known delivery agents having the noted action on release. Another approach comprises the use of protamine (or a protamine-like compound) to alter the surface of the bladder, therereby fostering access. Alternatively, to enhance access. The subject is first treated with protamine or a protamine-like agent is followed by administration of the active antimuscarinic agent in combination with a glycosamine. In yet another embodiment, the endogenous intravesical GAG compartment is exchanged with or replaced by an exogenously applied mixture that incorporates the antimuscarinic composition of this invention.
The present invention also provides a method for irreversibly inhibiting a muscarinic cholinergic response in urinary bladder cells, bladder tissue or the whole organ, comprising providing to the cells, tissue or organ an effective anticholinergic concentration of a composition as described herein.
Also provided are kits for administering the compositions, which comprise the antimuscarinic agent and the supplies that are needed to prepare the composition for intravesical administration and equipment for administering the composition.